Duloxetine is a serotonin and noradrenaline reuptake inhibitor, and it has therapeutic use in the fields of depression and urinary incontinence.
Preparation of duloxetine and its intermediate products is described for example in patents EP 0 273 658, U.S. Pat. No. 5,362,886, WO 2004/005239, US 2003/0225153. The basic reaction used is presented in the following Scheme 1.

Most syntheses use the already optically active intermediate product II, i.e. (S)-N,N-dimethyl-3-hydroxy-3-(2-thienyl)propylamine, for this reaction. During synthesis of many optically active compounds, resolving or obtaining optically pure intermediates result in better yields than resolution of the final products. However, with respect to synthesis of duloxetine, it has turned out that during further processing according to Scheme 1, racemization happens again. Thus, the obtained resulting product is not enantiomerically pure and it is necessary to recrystallize it again. This naturally decreases the yield of the process.
A solution of undesirable racemization during the reaction according to Scheme 1 is offered in patent application WO 2004/056795 A1. The authors choose a method of preparation of racemic duloxetine and its resolution with an appropriate chiral acid. Using this procedure, they indeed prevent possible racemization but, on the other hand, they increase losses because they also process the undesired (R)-enantiomer until the final stage.
In the original patents, the reaction according to Scheme 1 was performed under catalysis with strong bases such as sodium hydride or lithium hydride. These bases are relatively expensive and it is necessary to avoid moisture when they are used because they can react with it vigorously.
In the application WO 2004/056795, a method for performing the reaction according to Scheme 1 is also published, wherein the use of a phase-transfer catalyst allows to perform the reaction also with weaker bases such as alkali metal hydroxides.
Preparation of the compound I is described in Example 2 (preparation 2) of U.S. Pat. No. 5,362,886. The final product results from action of concentrated hydrochloric acid on a solution of the duloxetine base in ethyl acetate. An inoculating crystal of compound I is added to the acidified reaction mixture and the mixture is diluted with more ethyl acetate; after stirring for 30 minutes the mixture is again concentrated to the original volume and then stirred at room temperature for 1 hour and at 0° C. for 1 hour.
However, during reproduction of this procedure, it has turned out that the solution starts to turn red during processing, which resulted in a contaminated product. In addition, if the suspension described in U.S. Pat. No. 5,362,886 was to be obtained in the given yield, it was necessary to further prolong the stirring, which resulted in further accumulation of impurities. Experiments using different amounts of hydrochloric acid also were not successful.
The present invention presents a comprehensive solution of manufacture of duloxetine, which eliminates or minimizes all mentioned disadvantages.